Genetic polymorphic variations such as SNPs are valuable tools for deciphering mechanisms of biological functions and understanding the underlying basis of human diseases. See generally, Cooper et al. in The Metabolic and Molecular Bases of Inherited Diseases, 1:259-291 (1995), Scriver et al., eds., McGraw-Hill, New York. Single-nucleotide polymorphisms (SNPs) are small variations in genomes. They are among the most common forms of human genetic variations. A large number of monogenic human diseases are associated with genetic polymorphic variations such as SNPs in the so-called susceptibility genes. For example, polymorphic variations in the coagulation factor gene F5 have been linked directly to deep-vein thrombosis. See Bertina et al., Nature, 369:64-67 (1994). SNPs in the Apolipoprotein E gene correlate with the risk of Alzheimer's disease. See U.S. Pat. No. 5,773,220.
Genetic polymorphic variations are also associated with varying response to drugs and natural environmental agents. See generally, McCarthy et al., Nat. Biotechnol., 18:505-508 (2000); Nebert, Am. J. Hum. Genet. 60:265-271 (1997); and Puga et al., Crit. Rev. Toxicol. 27(2):199-222 (1997). Pharmacogenomic studies have found a large number of SNPs responsible for differing drug response. For example, variants in the 5-lipoxygenase gene, which codes for an anti-asthma drug target, have been linked to variations in drug response. See Drazen et al., Nat. Genet. 22:168-170 (1999). In addition, genetic variants in the drug-metabolizing enzyme thiopurine methyltransferase correlate with adverse drug reactions. See Krynetski et al., Pharm. Res., 16:342-349 (1999).
Since proteins are intimately involved in essential biological functions and drug metabolism, the apparent nexus between genetic polymorphic variations and human diseases and drug response is not at all surprising because any gene sequence changes may potentially affect gene expression and protein functions. For example, SNPs in exons may lead to different protein sequences exhibiting altered protein activities (e.g., sickle cell anemia). SNPs in exons and thus mRNAs may also affect the splicing, processing, transport, translation, or stability of the mRNAs. See e.g., Cooper et al., in The Metabolic and Molecular Bases of Inherited Diseases, 1:259-291 (1995), Scriver et al., eds., McGraw-Hill, New York. SNPs in exons may also alter mRNA secondary or tertiary structures, i.e., mRNA folding, and thus affect post-transcriptional gene regulation. See Shen et al., Proc. Natl. Acad. Sci. USA, 96:7871-7876 (1999).
Polymorphic variations in non-coding regions have also been linked to diseases and other phenotypic effects. For example, SNPs in introns can affect mRNA splicing and thus alter gene expression. See e.g., Otterness et al., J. Clin. Invest., 101(5):1036-44 (1998); Hayashi et al., Growth Horm. IGF Res., 9:434-437 (1999); Tsai et al., Biochem. Mol. Med., 61:9-15 (1997); Yu et al., Atherosclerosis, 146:125-31 (1999); Nemer et al., Blood, 89:4608-16 (1997); States et al., Mutat. Res., 363:171-7 (1996). Genetic variations in intronic sequences may also influence gene transcription or interactions between gene transcription products and other cellular machines. Likewise, polymorphic variations in transcriptional regulatory regions of a gene may alter transcription pattern of the gene. See McGuigan et al., Osteoporos. Int., 11:338-43 (2000); Arnaud et al., Arterioscler. Thromb. Vasc. Biol., 20:892-898 (2000).
Very often, a genetic polymorphic variant alone does not cause any detectable effect on gene expression or gene function. However, it may act in concert with other known or unknown polymorphic variants in the gene and cause cumulative or synergistic effect sufficient to alter gene expression pattern or the properties of the protein encoded by the gene. Even if a particular genetic polymorphic variant does not contribute to any changes in gene expression or protein function, it may be near or linked to one or more other genetic variants that directly cause phenotypic defects. Therefore, by identifying such genetic variants, one could reasonably predict the phenotypic effect in an individual having such genetic variants. In addition, one can also identify haplotypes, that is, combinations of genetic variants in a particular gene or chromosome present in an individual. Haplotypes represent patterns of genetic variations and are important tools for genetic analysis and diagnosis.
Indeed, genetic polymorphic variations such as SNPs and haplotypes containing SNPs are invaluable genetic markers for a variety of applications. For example, genetic polymorphic variations are useful in genetic analysis for studying polymorphic allele segregation and polymorphism origins. In addition, genetic polymorphisms can be used as markers in population study, and in forensic medicine. More importantly, SNPs can be particularly useful in genetic diagnosis for identifying individuals predisposed to certain diseases. See e.g., U.S. Pat. Nos. 5,994,080, 5,942,390, 5,773,220, and 5,736,323. Further, SNPs can also be valuable tools for predicting an individual's response to drug treatment or other exogenous interventions.
Thus, there is need in the art to identify additional SNPs, particularly those associated with defined phenotypes like depression and/or neurological disorders.
Depression is thought to affect around twenty million Americans every year. The economic impact of depression is difficult to estimate, but reports indicate that the disease was responsible for an economic burden of approximately 44-52 billion dollars in 1990 and 83 billion dollars in 2000, in the United States alone (Greenberg et al. J. Clin. Psy. 23:1465-75 (2003)). Depression manifests itself in many different ways including persistent sad mood, loss of interest or pleasure in once enjoyable activities, significant change in appetite or body weight, sleep disorders, physical slowing or agitation, loss of energy, feelings of worthlessness, inappropriate guilt, difficulty thinking, difficulty concentrating, malaise, and recurrent thoughts of death or suicide. The families and friends of depressed individuals are often profoundly affected by the disease.
Depression is typically diagnosed as major depressive disorder (unipolar major depression, bipolar disorder (manic-depressive illness), and dysthymic disorder (dysthymia). There are a number of subtypes of these major categories of depression. Diagnosis of these mental disorders is based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (American Psychiatric Association; Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), Washington, D.C., American Psychiatric Press, 1994).
Major depression is associated with low mood, low energy and motivation, insomnia, and feelings of worthlessness and hopelessness. Bipolar disorder is a severe psychiatric disorder that affects approximately 1% of the world's population (Goodwin, F. K. and Jameson, K. R. Manic-Depressive Illness, Oxford Univ. Press, New York (1990)). It is characterized by extreme swings in mood between mania and depression. Mania is accompanied by euphoria, grandiosity, increased energy, decreased need for sleep, rapid speech, and risk taking. Psychosis can occur in either state, and there is a 17% lifetime risk for suicide. Dysthymic disorder is considered a milder form of depression with symptom similar to that of major depression.
The etiology of depression is currently unknown, but epidemiological studies argue for a strong genetic component. Family studies indicate an approximately 7-fold increase in risk to first-degree family members (Tsuang, M. T. and Faraone, S. V. (1990) The Genetics of Mood Disorders, Johns Hopkins Univ. Press, Baltimore). Twin studies find an average 4-fold increase in risk to monozygotic vs. dizygotic twins. The mode of genetic transmission is unclear. Although some studies have supported the presence of autosomal dominant major loci (Spence, M. A. et al. Am. J. Med. Genet. 60:370-376 (1995); Rice, J. et al Arch. Gen. Psychiatry 44:441-447 (1987)), it has also been argued that bipolar disorder is oligogenic with multiple loci of modest effect.
Although initial attempts at linkage studies met with inconsistent replication (Egeland, J. A. et al. Nature 325:783-787 (1987); Kelsoe, J. R. et al. Nature 342:238-243 (1989); Baron, M. et al. Nature 326:289-292 (1987); Baron, M. Soc. Biol. 38:179-188 (1991)), more recently, the accumulation of multiple studies of larger family sets has led to the reproducible identification of several genetic loci associated with depression. These include 4p, 12q, 13q, 18, 21q, and Xq among others (Blackwood, D. H. et al. Nat. Genet. 12:427-430 (1996); Dawson, E. et al. Am. J. Med. Genet. 60:94-102 (1995); Detera-Wadleigh, S. D. et al. Proc. Natl. Acad. Sci. USA 96:5604-5609 (1999); Berrettini, W. H. et al. Proc. Natl. Acad. Sci. USA 91:5918-5921 (1994); Freimer, N. B. et al. Nat. Genet. 12:436-441 (1996); Straub, R. E. et al. Nat. Genet. 8:291-296 (1994); Pekkarinen, P. et al. Genome Res. 5:105-115 (1995); Craddock, N. & Jones, I. J. Med. Genet. 36:585-594 (1999); Craddock, N. & Jones, I. Br. J. Psychiatry 41:s128-s133 (2001)). Linkage between bipolar disorder and chromosome 12q23-12q24 has been reported (Green, E. K. et al. Am. J. Med. Genet. 96:545 (2000); Morissette, J. et al. Am. J. Med. Genet. 88: 567-587 (1999); Ewald, H. et al. Psychiatr. Genet. 8:131-140 (1998); Degan, B. et al. Mol. Psychiatry 6:450-455 (2001); Detera-Wadleigh, S. D. et al. Am. J. Med. Genet. 88:255-259 (1999); Jacobsen, N. et al. Psych. Genet. 6:195-199 (1996); Rice, J. P. et al. Am. J. Med. Genet. 74:247-253 (1997)).
In view of the economic and emotional costs associated with depression, there is a need to identify genes associated with depression for diagnostic and therapeutic purposes.
The present invention relates generally to depression. More specifically, the present invention relates to a human depression predisposing gene, specifically the AKAP9 (A-Kinase Anchor Protein 9) gene, a mutant allele of which is associated with susceptibility or predisposition to depression. More specifically, the invention relates to a single nucleotide polymorphism within the AKAP9 gene and its use in the diagnosis of predisposition to depression. The invention also relates to the prophylaxis and/or therapy of depression associated with altered AKAP9. The invention further relates to the screening of drugs for depression therapy. Drugs which modulate AKAP9 bioactivity are expected to have therapeutic value in depression. Finally, the invention relates to screening the AKAP9 gene for mutations/alterations, which are useful for diagnosing predisposition to depression.